We completed a study examining the neuroprotective effects of a naturally occurring antioxidant, astaxanthin, in a rodent model of stroke. Astaxanthin is found in the shells of many crustaceans and is available as a dietary supplement. Our findings show that ATX present at the time of an ischemic event decreases the ischemic damage and many associated markers of cell death. This work was published in FASEB J. In collaboration with Dr. Nigel Grieg (NIA), we have investigated the neuroprotective effects of activating the Glucagon-like peptide-1 receptor (GLP-1R). This year we published the protective effects of GLP1R receptor agonists (GLP-1 and exendin-4) against neurodegeneration in rodent models of stroke and Parkinsons disease and the results. We are currently developing an AAV vector expressing exendin-4 for further exploring therapeutic strategies including inducible expression. In addition, we are identifying methods of delivery AAV via the ventricular system for gene delivery of Exe-4 in several models of neurodegeneration including stroke, Alzheimers and ALS. This work is ongoing. As part of a collaboration on a primary project of Dr. Barry Hoffer (NIDA) and Mart Saarma (U Helsinki), we are examining the neuroprotective effects of conserved dopaminergic neurotrophic factor (CDNF) in a mouse model of Parkinsons disease. We are examining whether CDNF protein or an AAV-CDNF can confer neuroprotection and neuroregeneration in against neurotoxicity caused by MPTP. This work is ongoing. We completed and published a study demonstrating the neuroprotective effects of Mesencephalic astrocyte-derived neurotrophic factor (MANF)-mediated in a rodent model of stroke. Using an AAV vector expressing MANF, we can reduce ischemic brain injury and improved behavioral outcome. Using this model and evidence that MANF may be a mediator of the unfolded protein response (UPR) to endoplasmic reticulum stress, we are examining the molecular mechanism of MANF neuroprotection. We are also conducting cell culture experiments and C. elegans experiments to address the protective mechanisms of MANF as it relates to its function in ER stress. The phenomenon of ER stress occurs in many diseases beyond neurodegenerative and understanding its role may lead to broader therapeutic strategies. This work is ongoing. Our section has previously demonstrated the ability of Bone Morphogenetic Protein 7 (BMP7) to promote neuroregeneration. As a continuation of this work, we have used an in vitro model of primary cortical neurons to show that BMP7changes the appearance of axons and dendrites and have linked this to the change in extracellular matrix proteins. This project is ongoing.